Currently, all tissue augmentation fillers approved by the United States Food and Drug Administration are derived from collagen. Approximately 3-5% of human subjects show serious allergic reactions to bovine collagen, thus requiring careful testing before using these fillers in any particular subject.
Hyaluronic acid, also referred to as “HA,” is a naturally occurring, water soluble polysaccharide that is a major component of the extra-cellular matrix and is widely distributed in animal tissues. Naturally occurring HA generally has a molecular weight range of about between 6×104 to about 8×106 Daltons. It has excellent biocompatibility and does not give a foreign body or allergic reaction when implanted into a subject.
Methods of preparing commercially available hyaluronan are well known. Also known are various methods of coupling HA and cross-linking HA to reduce the water solubility and diffusibility of HA, and to increase the viscosity of HA. See, for example, U.S. Pat. Nos. 5,356,883 and 6,013,679, the entire teachings of which are incorporated herein by reference. Further, many forms of HA have been employed, e.g., as surgical aids to prevent post operative adhesions of tissues, as adjuncts to synovial fluid in joints, as fluid replacement and/or surgical aids in ophthalmic surgery, as a scaffold for tissue engineering in vitro or guided tissue regeneration or augmentation in vivo, and the like.
The use of such HA products suffers several defects, however, in particular, a tradeoff between in vivo properties and surgical usability. For example, HA that is sufficiently chemically modified or crosslinked to have desirable in vivo mechanical and biostability properties can be so highly viscous that injection through fine needles is difficult or impossible. Conversely, HA that is injectable can have inferior in vivo biostability and mechanical properties.
Further, there is high current interest in employing chemically modified HA for vehicle-assisted time release delivery of bioactive agents including, for example, therapeutic agents or drugs and biological probes. A major challenge is the development of a delivery vehicle that will provide the appropriate level of bioavailability of a therapeutic agent at the affected area to achieve a desired clinical result, yet also have a desirable balance of in vivo mechanical and biostability properties balanced with surgical/administrative usability. The bioavailability of a drug depends upon the nature of the drug, the drug delivery vehicle used, and the route of delivery, for example, oral, topical, transdermal, mucosal, administration by injection, administration by inhalation, or administration by a combination of two or more of these routes. The bioavailability may be low as a result of, for example, the degradation of the drug by metabolic processes, rapid or uneven degradation of the delivery vehicle, rapid or uneven release of the drug from the delivery vehicle, and the like. These can be accompanied by similar problems of frequency of administration, difficulty of administration, e.g., difficulty of injection, biodegradation, and the like. In addition to the difficulties noted above, frequent administration of insufficiently stable drug delivery vehicles can lead to variations in drug delivery, leading to an increase in the occurrence of damaging side effects, a decrease in therapeutic benefit, and the like.
Therefore, there is a need for a HA composition that overcomes or minimizes the above referenced problems.